Physical activity and cognitive function in individuals over 60 years of age: a systematic review

Introduction

An unprecedented growth of the aging population is taking place. For example, in 2000, 28% of adults aged 65 and older were expected to reach at least 90 years; this number is projected to rise to 47% by 2050, representing a near-doubling of the elderly population to 80 million.¹ The economic impact of an aging population on health care systems is potentially overwhelming, in particular for age-related disorders such as dementia. In 2005, approximately 29.3 million individuals with dementia incurred a cost of US$315 billion worldwide, with the highest costs in North America and Europe.² Since then, the global prevalence of dementia has increased to more than 34 million, and the bulk of disease burden is shifting from developed to developing countries.³ As such, effective interventions to help reduce the prevalence of cognitive disability in the elderly are needed. One possible intervention that deserves consideration is physical activity, an adjunct that has many well established health benefits and may serve to enhance quality of life.⁴ However, the effect of exercise on cognitive function remains controversial. A National Institutes of Health conference review of age-related cognitive decline reported a marginal benefit of exercise in one small randomized controlled trial (RCT) and eight observational studies showing a possible decrease in cognitive decline with exercise.⁴ A Cochrane review of eleven randomized clinical trials reported that aerobic exercise improved cognition in a few domains, including cognitive speed and auditory/visual attention, in subjects without cognitive impairment.⁵ Another Cochrane review of exercise in patients with dementia found only two relevant studies and concluded that there was insufficient evidence of benefit from exercise in these patients.⁶ These reviews did not find sufficient evidence to endorse exercise as beneficial to cognition, but were, overall, narrow in scope. However, other reviews have determined different results; for example, a more recent review concluded that an exercise regimen of one hour at least 3 times per week for 6 weeks was beneficial in subjects with or without cognitive impairment.⁷ We have performed a systematic review to assess the validity of the current data, including more recent randomized clinical trials and observational studies that provide a broad-based view of the effect of exercise on cognition in elderly persons.

Materials and methods

Studies

All RCTs with at least 30 participants and lasting at least 6 months, and all observational studies (prospective cohort studies, case-control studies, and longitudinal studies) with at least 100 participants and lasting at least one year, which were published in the English language on or after January 1, 2000 until August 15, 2012, and met the inclusion criteria were considered (Table 1).

Table 1 Characteristics of included studies

Participants

Only participants who were 60 years or older were included in this review. Studies examining the effects of physical activity in elderly individuals with or without mild cognitive impairment or cognitive disease (such as Alzheimer’s disease or other dementia) were included. Studies including participants with systemic disorders such as chronic obstructive pulmonary disease or diabetes, those with traumatic brain injury, or comorbidities that precluded participation in exercise programs were excluded.

Interventions

Physical activity was considered to be any aerobic or isometric exercise of any intensity, duration, or frequency that aimed to improve overall physical fitness. For randomized clinical trials, active interventions such as aerobic exercise, isometric exercise, health education programs with monitored exercise sessions, or physical therapy-driven exercise treatments were compared with control groups that received no intervention (Table 2).

Table 2 Design, methods, interventions and assessment, and outcome measures in included studies Abbreviations: 3MS, Modified Mini-Mental State; ACT, Adult Changes in Thought; ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive subscale; BMI, body mass index; BP, blood pressure; CASI, Cognitive Abilities Screening Instrument; CSID, Community Screening for Dementia; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; Health ABC, Health, Aging, and Body Composition; GDS, Geriatric Depression Scale; YPAS, Yale Physical Activity Survey; LIFE-P, Lifestyle Interventions and Independence for Elders Pilot; MDB, Mental Deterioration Battery; MMSE, Mini-Mental State Examination; RBMT, Rivermead Behavioural Memory Test; FCSRT, Free and Cued Selective Reminding Test; MRI, magnetic resonance imaging; TMT, Trail Making Tests; SPMSQ, Short Portable Mental Status Questionnaires; 3GM, Modified Mini-Mental Status Examination; MoVIES, Monongahela Valley Independent Elders Survey; SPPB, Short Physical Performance Battery; RCT, randomized controlled trial; WHICAP, Washington Heights-Inwood Columbia Aging Project; IQCODE, Informant Questionnaire on Cognitive Decline in the Elderly; AD, Alzheimer’s disease; RM, repetition maximum; IU, Indiana University.

Outcome measures

The primary outcome measurement was cognitive function. The most commonly used tests included the Mini-Mental State Examination (MMSE) or Modified Mini-Mental State Examination (3MS), both of which give a global measure of cognitive function, and the Cognitive Ability Screening Instrument (CASI), which indicates the presence or absence of dementia (Table 2). A neuropsychological test battery with published criteria (such as the Mayo Clinic Criteria for dementia) utilized by an expert panel in diagnosing the presence or absence of dementia was also accepted.

Search methods for study identification

We searched PubMed, Medline, CINAHL, the Cochrane Controlled Trials Register, and the University of Washington School of Medicine Library database on August 15, 2012 for studies published in English on or after January 1, 2000. We used MeSH terms to find studies of physical activity including: adaptation, physiological/physiology*, exercise/physiology*, and physical fitness/physiology*. To reduce our findings to studies that measured cognition or incidence of cognitive disease and physical fitness, we searched using the following MeSH terms: cognition, cognitive disease, cognition disorders/prevention and control, cognition/physiology*, brain/physiology*, memory/physiology*, motor activity/physiology*, neuropsychological tests, dementia, and Alzheimer’s disease. To further reduce our findings to studies that focused on elderly human subjects, we searched using the MeSH terms: humans, elderly, aged, aging, old, older, and geriatric.

Data collection

Two reviewers screened the titles and abstracts of all studies identified by the search (71 studies) and irrelevant studies were excluded. Relevant papers were then assessed in full for inclusion eligibility.

Quality assessment

Two reviewers assessed the methodological quality of the selected studies. The Agency for Healthcare Research and Quality Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews was used to perform quality assessment of the trials. These criteria include information on sampling method, outcome measurement, intervention, and reporting of biases and limitations. A summary of these criteria is presented in Table S1.

Results

Description of studies

Seventy-one studies were identified using the database as described in the Materials and methods section. After removal of duplicates, 57 full-text articles were assessed for eligibility (Figure 1). Thirty studies were excluded, leaving 27 studies that were eligible for review according to the prespecified criteria (Figure 1). A total of 30,572 subjects over 60 years of age were included in the 27 studies that met our inclusion criteria. The characteristics of the studies included in this review are described in Tables 1, 2, and 3. The 30 excluded studies are described in Table S2.

Figure 1 Description of studies which were identified, screened, and included in the systematic review.

Table 3 Results of included studies Abbreviations: RBMT, Rivermead Behavioural Memory Test; RCT, randomized controlled trial; MMSE, Mini-Mental State Examination.

Type of included studies, and quality and bias

Fifteen prospective cohorts, ten RCTs, one case-control study, and one observational study met the criteria for review (Table 1). Eight studies were considered to be of high quality. One study,⁸ an RCT, was considered to be of fair quality, rather than high, because approximately 12% of patients dropped out of the study and could not be assessed. The majority of studies (15/27) were of fair quality while three were considered poor quality. The overall risk of bias was moderate for the majority of the studies (16/27) with eight considered low risk and three at high risk of bias (Table 1). Seven of ten RCTs included in the review were generally of higher quality and exhibited lower bias overall (Table 1). However, the RCT evidence included in this review displayed potential bias in the form of lack of allocation concealment and lack of assessor blinding, as well as lack of participant blinding, since participants were randomized into either a physical activity group or an education/noninterventional control group. In these studies, the evidence tended to be of lower quality with potentially higher bias due to possible unreliable self-reporting, potential influence of interviewers, and use of questionnaires and interviews to assess physical activity rather than direct measurements.

Selection bias

Most of the studies included in this review were at risk of selection bias, because the participants were largely drawn from specific population samples (hospital, city, region). Selection bias may also have occurred due to the fact that the decision to partake in physical activity may be linked to potentially confounding lifestyle choices. Further, follow-up visits were required for most of the studies, and would require the ability to commute to study centers. Potential participants were excluded if they had chronic disease, such as cardiovascular disease, pulmonary disease, diabetes, physical disability, or depression. Therefore, the study data cannot be extrapolated to such individuals.

Effect of physical activity intervention

Twenty-seven studies (Table 1) met the inclusion criteria for this review. Of these, 26 studies reported a significant association between physical activity and cognitive function in late life (Tables 3 and 4). Of the ten RCTs, nine showed a positive correlation and one showed a nonsignificant correlation.⁹ Although these studies included both male and female subjects, one RCT by Klusmann et al¹⁰ enrolled only elderly healthy female subjects. As compared with controls, the authors also found a significant benefit of physical exercise (aerobic training with a bicycle ergometer or treadmill) in this elderly female population. Therefore, the majority of the studies concluded that physical activity in later life confers a protective effect on cognition in elderly subjects. Additionally, there were five studies^11–16 that reported a dose-response association between physical activity and cognitive function.

Table 4 Association between physical activity and cognitive function in selected studies Abbreviation: N/A, not applicable.

Discussion

This review examined the effect of physical activity in late life on age-related cognitive decline in older individuals with normal cognitive function or mild cognitive impairment at baseline. When selecting studies for review, the assumption was made that there is no difference in effect on cognition between different physical activities, ranging from aerobic to isometric exercises. As such, all types of physical activity program interventions were accepted in the study selection process. The data indicate that this assumption was generally correct; 26 of 27 studies showed a significant association between physical activity and cognitive decline, whereby an increased level of physical activity resulted in attenuation of cognitive decline and cognitive disease (Tables 3 and 4). In the ten RCTs evaluated in this review, the different interventions included aerobic and isometric exercise, weight training, and Tai Chi. Eight of these studies showed a significant outcome benefit, with one study showing a nonsignificant correlation (Table 4). Although these trials were not designed to determine a threshold effect or dose-response effect, there were five prospective studies suggesting a dose-response relationship in the level of benefit found with exercise,^11–16 thus providing additional credence to the specificity of the effects of exercise on cognitive function.

Implications of evidence quality

Despite the preponderance of positive studies, only nine of the 27 studies were considered to be of high quality and the overall risk of bias was moderate in 16 studies (Table 1). Many studies included in this review relied on self-reporting to assess exercise habits, rather than using a more objective means of measuring physical activity.

In the studies evaluated in this review, outcome measures of cognitive performance were wide-ranging and measured different aspects of cognitive function (Table S3). Several studies used a neuropsychological test battery to test multiple aspects of cognitive function, while other studies used only one or two cognitive tests. Data heterogeneity may have confounded identification of the domains of cognitive function that were most affected by exercise. We standardized the cognitive metrics, inclusion criteria, and outcomes in this review as much as possible, which may have enabled us to ascertain an association between exercise and a few specific domains of cognitive function, such as the MMSE and Cognitive Inhibition (Stroop Color and Word Test). In the nine studies considered to be of higher quality, seven were RCTs^9,10,17–21 and two were prospective studies.^14,22 In these studies, a positive correlation was evident between physical activity in later life and cognition in the elderly subjects evaluated.

Similarly, the types of physical activity interventions used in the studies reviewed were wide-ranging, from aerobic or isometric physical activity, or combinations of both. Given the variability in physical activity interventions and the measures of cognitive function, it was not possible to determine a distinct relationship between specific types of physical activity and improvements in specific cognitive domains. As such, better standardization of the types of physical activity interventions could have clarified the specific causal relationships more effectively.

The durations of the included studies ranged from 6 months to several years. It is possible that improvements in some aspects of cognitive function occur shortly after completion of an exercise program, while improvements in other aspects may take several months or years to develop. For example, when using the 3MS or MMSE as one of the outcome measures, there was only one study showing a positive effect at 12 months²⁰ whereas the other two did not;^8,9 and five studies demonstrated the positive impact of exercise on cognitive function over the course of more than 12 months.^{12,16,23–25} The positive effect of exercise on cognitive speed^26,27 and cognitive inhibitory function²¹ can be observed as early as 6 months. These observations highlight the time-specific effect of physical activity on each cognitive domain. Of interest, a study by Segal et al²⁸ found that the acute effects of exercise enhance learning ability in patients with mild cognitive impairment and subjects with normal cognition. These investigators postulated that exercise could function as a stimulus for memory consolidation due to its stimulatory effects on the locus coeruleus and consequent release of norepinephrine. They found that exercise, conducted acutely after a period of learning, significantly increased the release of endogenous norepinephrine in both types of study subjects and resulted in retrograde enhancement of memory.²⁸ As such, acute exercise, associated with periods of learning, may be a positive therapeutic intervention for cognitive decline in elderly subjects. In future research, it would be important to determine which forms of exercise affect specific domains of cognition and, also, the latency and duration of effect.

An exclusion criterion for this review was the presence of specific underlying conditions or diseases in the study population (such as chronic obstructive pulmonary disease, diabetes, traumatic head injury, cardiovascular disease, or depression). Therefore, our findings cannot be extrapolated to individuals with chronic underlying conditions in whom improvements in cognitive performance following a program of physical activity may be diminished or not apparent. For example, Hoffman et al²⁹ published an RCT in which a program of physical activity failed to improve neurocognition in elderly subjects with clinical depression. This also has implications when assessing the overall effectiveness of physical activity in later life on cognitive performance in the very elderly, since a significant proportion of this population suffers from chronic conditions that may impede improvements in cognitive function following a physical activity regimen.

Neural plasticity: possible mechanisms for effect of exercise on cognition

Decline in cognitive function is one of the hallmarks of the aging process. The concept of neuronal structural plasticity in learning and memory processes^30,31 suggests that cognitive decline in aging may be associated with dysregulation of brain plasticity.³² Mahncke et al³³ demonstrated that elderly subjects with normal cognitive function had enhancement of memory following an intensive, plasticity-based computer training program. Physical exercise^34,35 promotes positive neuroplasticity, increases cognitive reserve and higher neuronal connection density, and results in improved cognitive function. On the contrary, negative neuroplasticity results from physical inactivity, poor nutrition, substance abuse, and social isolation, decreases cognitive reserve, and inhibits formation of neuronal connections, leading to reduced cognitive function.^1,36,37

Cerebral blood flow

While both aerobic and isometric physical activity are thought to confer improved cognition, studies suggest that aerobic exercise may be more effective in slowing degenerative neurological processes that lead to age-related cognitive decline and dementia.³⁸ How might aerobic exercise contribute to neuroprotection? Many processes leading to cognitive decline stem from atherosclerotic or cerebrovascular conditions that produce cerebral hypoperfusion.³⁹ Ruitenberg et al found that higher cerebral blood flow velocity was significantly associated with less cognitive decline and lower velocity was related to Alzheimer’s disease.⁴⁰ The capacity of long-term aerobic exercise to mitigate the effects of vascular disease is well established,⁴¹ and may be an important mechanism of cognitive preservation due to exercise. Other mechanisms of neuronal enhancement with exercise include the role of neurotransmitters, changes in brain vasculature, and effects of neurotrophins.^42,43 These processes, individually or together, may attenuate neurodegeneration and confer neuroprotective benefits, resulting in improved cognitive function.

Angiogenesis

Angiogenesis, the formation of vasculature by pre-existing endothelial cells, occurs in the brain during development but declines with age. Animal models have shown that exercise induces angiogenesis of small-vessel vasculature in the cerebellum, motor cortex, and hippocampus. Animal studies have shown that the hippocampus, which is essential for memory formation, is highly oxygen-dependent. Consequently, hippocampal angiogenesis may explain improvements in learning and memory following sustained, moderate-level physical activity. Maximal oxygen consumption increases with aerobic exercise, which is thought to be effective in promoting brain angiogenesis in experimental animals (rodents⁴³ and monkeys⁴²). Therefore, aerobic exercise may have more impact on cognitive performance than isometric exercise.

Effects of cytokines, neurotrophins, and brain volume

Neurotrophins are endogenous brain proteins that serve to promote neuroplasticity, and are thought to play a central role in response to physical activity.⁴⁴ Granulocyte colony-stimulating factor (G-CSF) and brain-derived neurotrophic factor (BDNF) are implicated in mediating increases in cerebral gray matter volume and hippocampal volume, respectively,⁴⁵ and enhancing cognitive performance by optimizing cognitive reserve, increasing learning capacity, and streamlining memory processes.⁴⁵ The effect of G-CSF in subjects undergoing exercise protocols has been evaluated in several studies; plasma levels of G-CSF have been found to increase significantly after short bursts of aerobic exercise⁴⁶ as well as following periods of endurance exercise.⁴⁷ The role of G-CSF on neutrophil activation, proliferation, and survival is important for the immune response, thus illustrating the possible correlation with exercise in immunomodulation. BDNF is integral to differentiation, extension, and survival of neurons in the hippocampus, cortex, and cerebellum during brain development,^48–50 and increases levels of synaptophysin and synaptobrevin, substances that aid transport of neurotransmitter vesicles. Support for this mechanism comes from animal studies showing that regulation of BDNF is associated with physical activity, as demonstrated by increased BDNF gene expression in rats as a result of running,^25,51 with diminished or nonapparent effects when BDNF production is blocked.⁵² The role of BDNF in cognitive impairment remains inconclusive, with studies reporting different results.^53,54 Nevertheless, the importance of BDNF in preservation and enhancement of cognitive function in humans was demonstrated by Erickson et al,⁴⁵ who found that decreased levels were associated with age-related decline in hippocampal volume, and that aerobic exercise increased BDNF, hippocampal and temporal lobe volumes, and spatial memory. The association between BDNF level, hippocampal volume, and dementia was also established at the molecular level in subjects with BDNF gene polymorphism.⁵²

Conclusion

There is evidence suggesting that physical activity in later life is beneficial for cognitive function in elderly persons. These benefits include enhancement of existing cognitive function and maintenance of optimal cognitive function, as well as prevention or delayed progression of cognitive diseases, such as Alzheimer’s dementia or other neurocognitive disorders. However, the majority of the evidence included in this review was of medium quality, and the overall risk of bias in the studies used in this review is moderately high. Despite the variable quality of the evidence, most of the data supports the concept that moderate-level physical activity in late life may improve cognitive function and delay the onset of debilitating cognitive disease in older persons. More evidence obtained from larger RCTs, preferably lasting for at least one year, is needed to confirm the association between physical activity in late life and improvements in cognitive function. Future research should focus on whether aerobic or isometric physical activity has a greater effect on cognition in the elderly, and which cognitive domains are most affected by physical activity. Additionally, research should be directed toward identifying and implementing exercise programs that would produce extended results on cognitive function in elderly patients.

Acknowledgment

The authors acknowledge the Department of Veterans Affairs, Queen’s University Belfast and The John Butler Lung Foundation for their support of this work.

Disclosure

The authors report no conflicts of interest in this work.

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Supplementary material

Table S1 Agency for Healthcare Research and Quality Methods summary ratings of quality of individual studies Source: Agency for Healthcare Research and Quality Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews (http://www.ahrq.gov/).

Table S2 Characteristics of excluded studies

Table S3 Grouping of cognitive tests and studies of cognitive function

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